Oncogene Addiction
Oncogenes signal excessively causing cell transformation, a phenotype characterized by proliferative growth independent of growth factors or anchorage and tumor formation in vivo. This is a reversible mechanistic paradigm such that inactivation of the oncogene by genetic or pharmacologic targeting should restore the cell to a state somewhat reminiscent of the untransformed state. However the widely observed effects of oncogene inactivation in the treatment of human cancers is the non-restorative apoptotic cell death. This phenomenon of oncogene addiction remains mechanistically unexplained.
The experience with the first generation of kinase inhibitors targeting kinase oncogenes has confirmed the important role of many of these oncogenes in human cancers, but has also revealed highly resourceful cellular mechanisms that can overcome the inhibitory effects of inhibitors, either through restoration of kinase signaling, or reprogramming of cellular circuitries to bypass the targeted kinase oncogene. Through several cycles of the acquisition of resistance and the development of resistance-breaking therapies, it is apparent that the addiction to the oncogene pathway perseveres. It is now apparent that the cellular addiction to the kinase oncogene may be the true driver of disease progression, not the oncogene itself.
We have been interested in understanding the molecular basis for the phenotype of oncogene addiction and have developed tools and reagents to explore this in unprecedented depth. These studies include modeling the development of the phenotype of transformation and addiction in an isogenic cell system and using powerful approach for interrogation including genomics, transcriptomics, proteomics, metabolomics, leading to highly plausible hypothesis for mechanistic testing.
